There is a fundamental gap in understanding the importance of brain insulin levels in stroke recovery. This gap is important because of the significance of brain insulin with regard to neuroplasticity and the anti-inflammatory, anti-thrombotic, vasodilatory and anti-apoptotic properties of insulin, which play a vital role in recovery from brain injury. The long-term goal is to understand the role of comorbidities on brain health, specifically cognitive aging. The objective of this application is to investigate the role of reduced brain insulin and the therapeutic potential of intranasal insulin on long-term stroke recovery (4 months post-stroke). Insulin resistance, which is a common comorbidity among stroke survivors, leads to a deficiency of insulin in the brain. The central hypothesis is that increasing brain insulin levels will improve stroke recovery. This hypothesis is based on preliminary data produced in the applicant?s laboratory. The rationale for the proposed research is that brain insulin levels affect neuroplasticity, and intranasal insulin may offer a new therapeutic approach to improve recovery from stroke. This hypothesis will be tested by pursuing two specific aims: 1) Determine the impact of insulin deficiency in the brain on stroke recovery, and 2) Ascertain the therapeutic potential of intranasal insulin therapy on stroke recovery. Under Aim 1, stroke recovery (cognitive, sensorimotor and motor function) is assessed in a comorbid mouse model (high-fat diet) with brain insulin deficiency, and in a non-comorbid mouse model (standard diet) treated with intranasal insulin affibody molecules, which reduce brain insulin levels, following an ischemic stroke. Under the second aim, intranasal insulin therapy is implemented post-stroke to enhance rehabilitation-induced neuroplasticity and improve stroke recovery. The approach is innovative, because it utilizes a comorbid animal model of ischemic stroke, assesses long-term stroke recovery up to 4 months post-stroke, and uses intranasal insulin as a therapy to enhance neuroplasticity and improve stroke recovery. The proposed research is significant because it is expected to lead to the establishment of intranasal insulin as a potential therapy to enhance stroke recovery. Ultimately, the COBRE also will provide the unique opportunity to work with clinical investigators to translate this basic science research into the clinic.